Upregulation of miR-99a is associated with poor prognosis of acute myeloid leukemia and promotes myeloid leukemia cell expansion.

Xiaohui Si,Feng-Chun Yang,Yingdai Gao,Jie Bai,Yahui Ding,Yuan Zhou,Hui Shi,Zizhen Chen,Yunan Li,Tao Cheng,Xing Hao,Xiaoyun Zhang

doi:10.18632/oncotarget.12947

Abstract

Leukemia stem cells (LSCs) can resist available treatments that results in disease progression and/or relapse. To dissect the microRNA (miRNA) expression signature of relapse in acute myeloid leukemia (AML), miRNA array analysis was performed using enriched LSCs from paired bone marrow samples of an AML patient at different disease stages. We identified that miR-99a was significantly upregulated in the LSCs obtained at relapse compared to the LSCs collected at the time of initial diagnosis. We also found that miR-99a was upregulated in LSCs compared to non-LSCs in a larger cohort of AML patients, and higher expression levels of miR-99a were significantly correlated with worse overall survival and event-free survival in these AML patients. Ectopic expression of miR-99a led to increased colony forming ability and expansion in myeloid leukemia cells after exposure to chemotherapeutic drugs in vitro and in vivo, partially due to overcoming of chemotherapeutic agent-mediated cell cycle arrest. Gene profiling and bioinformatic analyses indicated that ectopic expression of miR-99a significantly upregulated genes that are critical for LSC maintenance, cell cycle, and downstream targets of E2F and MYC. This study suggests that miR-99a has a novel role and potential use as a biomarker in myeloid leukemia progression.

Highlights

Acute myeloid leukemia (AML) is a genetically and clinically heterogeneous disease driven by a subpopulation of leukemia stem cells (LSCs) with selfrenewal properties that generate the bulk of leukemia cells [1,2,3]
MiRNA array analysis revealed that a series of miRNAs were upregulated in the Leukemia stem cells (LSCs) obtained at relapse compared to the LSCs collected at the time of initial diagnosis, and quantitative real-time PCR assays revealed that miR-99a was the most significantly differential miRNAs among the upregulated miRNAs in LSCs at relapse (Figure S1C and 1B)
The results revealed that miR-99a was significantly overexpressed in LSCs compared to paired non-LSCs in 14 out of 18 acute myeloid leukemia (AML) patients (Figure 1C)

Summary

Introduction

Acute myeloid leukemia (AML) is a genetically and clinically heterogeneous disease driven by a subpopulation of leukemia stem cells (LSCs) with selfrenewal properties that generate the bulk of leukemia cells [1,2,3]. The high number of LSCs or expression of an LSC related gene signature is independently associated with poor prognosis in AML, supporting the notion for LSCs as important targets for therapeutic intervention [1, 8, 9]. Epigenetic modifications such as DNA methylation, histone modifications and microRNAs (miRNAs), contribute significantly to the initiation, progression and/ or prognosis of leukemia [8]. MiRNAs are a family of 21-25-nucleotide small RNAs that negatively regulate gene expression at the post-transcriptional level [10]

Methods

Results

Conclusion